Clinical significance of cefazolin inoculum effect in serious MSSA infections: a systematic review.

Background: The cefazolin inoculum effect (CzIE) is a phenomenon whereby some MSSA isolates demonstrate resistance to cefazolin when a high bacterial inoculum is used for susceptibility testing. The clinical significance of this phenotypic phenomenon remains unclear. We conducted a systematic review to answer the following question: In patients with serious MSSA infection treated with cefazolin, does infection due to CzIE-positive MSSA isolates result in worse clinical outcomes than infection due to CzIE-negative MSSA isolates? Methods: Ovid MEDLINE, Embase, Cochrane CENTRAL, medRxiv and bioRxiv were searched from inception until 12 April 2023. Studies were included if they tested for CzIE in clinical isolates from MSSA infections in humans. Two independent reviewers extracted data and conducted risk-of-bias assessment. Main outcomes were treatment failure and mortality. Pooling of study estimates was not performed given the heterogeneity of patient populations and outcome definitions. Results: Twenty-three observational studies were included. CzIE presence amidst MSSA isolates ranged from 0% to 55%. There was no statistically significant mortality difference in two studies that compared MSSA infections with and without CzIE, with ORs ranging from 0.72 to 19.78. Of four studies comparing treatment failure, ORs ranged from 0.26 to 13.00. One study showed a significantly higher treatment failure for the CzIE group, but it did not adjust for potential confounders. Conclusions: The evidence on CzIE is limited by small observational studies. In these studies, CzIE did not predict higher mortality in MSSA infections treated with cefazolin. Our findings do not support CzIE testing in clinical practice currently.

Anaerobic Antibiotic Coverage in Aspiration Pneumonia and the Associated Benefits and Harms: A Retrospective Cohort Study.

BACKGROUND: Antibiotics with extended anaerobic coverage are used commonly to treat aspiration pneumonia, which is not recommended by current guidelines. RESEARCH QUESTION: In patients admitted to hospital for community-acquired aspiration pneumonia, does a difference exist between antibiotic therapy with limited anaerobic coverage (LAC) vs antibiotic therapy with extended anaerobic coverage (EAC) in terms of in-hospital mortality and risk of Clostridioides difficile colitis? STUDY DESIGN AND METHODS: We conducted a multicenter retrospective cohort study across 18 hospitals in Ontario, Canada, from January 1, 2015, to January 1, 2022. Patients were included if the physician diagnosed aspiration pneumonia and prescribed guideline-concordant first-line community-acquired pneumonia parenteral antibiotic therapy to the patient within 48 h of admission. Patients then were categorized into the LAC group if they received ceftriaxone, cefotaxime, or levofloxacin. Patients were categorized into the EAC group if they received amoxicillin-clavulanate, moxifloxacin, or any of ceftriaxone, cefotaxime, or levofloxacin in combination with clindamycin or metronidazole. The primary outcome was all-cause in-hospital mortality. Secondary outcomes included incident C difficile colitis occurring after admission. Overlap weighting of propensity scores was used to balance baseline prognostic factors. RESULTS: The LAC and EAC groups included 2,683 and 1,316 patients, respectively. In hospital, 814 patients (30.3%) and 422 patients (32.1%) in the LAC and EAC groups died, respectively. C difficile colitis occurred in 5 or fewer patients (≤ 0.2%) and 11 to 15 patients (0.8%-1.1%) in the LAC and EAC groups, respectively. After overlap weighting of propensity scores, the adjusted risk difference of EAC minus LAC was 1.6% (95% CI, -1.7% to 4.9%) for in-hospital mortality and 1.0% (95% CI, 0.3%-1.7%) for C difficile colitis. INTERPRETATION: Extended anaerobic coverage likely is unnecessary in aspiration pneumonia because it is associated with no additional mortality benefit, only an increased risk of C difficile colitis.

Evaluating in vivo effectiveness of sotrovimab for the treatment of Omicron subvariant BA.2 versus BA.1: a multicentre, retrospective cohort study.

BACKGROUND: In vitro data suggested reduced neutralizing capacity of sotrovimab, a monoclonal antibody, against Omicron BA.2 subvariant. However, limited in vivo data exist regarding clinical effectiveness of sotrovimab for coronavirus disease 2019 (COVID-19) due to Omicron BA.2. METHODS: A multicentre, retrospective cohort study was conducted at three Canadian academic tertiary centres. Electronic medical records were reviewed for patients ≥ 18 years with mild COVID-19 (sequencing-confirmed Omicron BA.1 or BA.2) treated with sotrovimab between February 1 to April 1, 2022. Thirty-day co-primary outcomes included hospitalization due to moderate or severe COVID-19; all-cause intensive care unit (ICU) admission, and all-cause mortality. Risk differences (BA.2 minus BA.1 group) for co-primary outcomes were adjusted with propensity score matching (e.g., age, sex, vaccination, immunocompromised status). RESULTS: Eighty-five patients were included (15 BA.2, 70 BA.1) with similar baseline characteristics between groups. Adjusted risk differences were non-statistically significant between groups for 30-day hospitalization (- 14.3%; 95% confidence interval (CI): - 32.6 to 4.0%), ICU admission (- 7.1%; 95%CI: - 20.6 to 6.3%), and mortality (- 7.1%; 95%CI: - 20.6 to 6.3%). CONCLUSIONS: No differences were demonstrated in hospitalization, ICU admission, or mortality rates within 30 days between sotrovimab-treated patients with BA.1 versus BA.2 infection. More real-world data may be helpful to properly assess sotrovimab's effectiveness against infections due to specific emerging COVID-19 variants.

More Than a Decade Since the Latest CONSORT Non-inferiority Trials Extension: Do Infectious Diseases Trials Do Enough?

More than a decade after the Consolidated Standards of Reporting Trials group released a reporting items checklist for non-inferiority randomized controlled trials, the infectious diseases literature continues to underreport these items. Trialists, journals, and peer reviewers should redouble their efforts to ensure infectious diseases studies meet these minimum reporting standards.

Comparative Effectiveness of First-Line and Alternative Antibiotic Regimens in Hospitalized Patients With Nonsevere Community-Acquired Pneumonia: A Multicenter Retrospective Cohort Study.

BACKGROUND: There are several antibiotic regimens to treat community-acquired pneumonia (CAP). RESEARCH QUESTION: In patients hospitalized to a non-ICU ward setting with CAP, is there a difference between first-line and alternative antibiotic regimens (ß-lactam plus macrolide [BL+M], ß-lactam [BL] alone, respiratory fluoroquinolone [FQ], or ß-lactam plus doxycycline [BL+D]) in terms of in-hospital mortality? STUDY DESIGN AND METHODS: This retrospective cohort study included consecutive patients admitted with CAP at 19 Canadian hospitals from 2015 to 2021. Taking a target trial approach, patients were categorized into the four antibiotic groups based on the initial antibiotic treatment within 48 h of admission. Patients with severe CAP requiring ICU admission in the first 48 h were excluded. The primary outcome was all-cause in-hospital mortality. Secondary outcome included time to being discharged alive. Propensity score and overlap weighting were used to balance covariates. RESULTS: Of 23,512 patients, 9,340 patients (39.7%) received BL+M, 9,146 (38.9%) received BL, 4,510 (19.2%) received FQ, and 516 (2.2%) received BL+D. The number of in-hospital deaths was 703 (7.5%) for the BL+M group, 888 (9.7%) for the BL group, 302 (6.7%) for the FQ group, and 31 (6.0%) for the BL+D group. The adjusted risk difference for in-hospital mortality when compared with BL+M was 1.5% (95% CI, -0.3% to 3.3%) for BL, -0.9% (95% CI, -2.9% to 1.1%) for FQ, and -1.9% (95% CI, -4.8% to 0.9%) for BL+D. Compared with BL+M, the subdistribution hazard ratio for being discharged alive was 0.90 (95% CI, 0.84-0.96) for BL, 1.07 (95% CI, 0.99-1.16) for FQ, and 1.04 (95% CI, 0.93-1.17) for BL+D. INTERPRETATION: BL+M, FQ, and BL+D had similar outcomes and can be considered effective regimens for nonsevere CAP. Compared with BL+M, BL was associated with longer time to discharge and the CI for mortality cannot exclude a small but clinically important increase in risk.

Ceftriaxone and the Risk of Ventricular Arrhythmia, Cardiac Arrest, and Death Among Patients Receiving Lansoprazole.

Importance: The combination of ceftriaxone and lansoprazole has been shown to prolong the corrected QT interval on electrocardiogram. However, it is unknown whether this translates to clinically important patient outcomes. Objective: To compare lansoprazole with another proton pump inhibitor (PPI) during ceftriaxone treatment in terms of risk for ventricular arrhythmia, cardiac arrest, and in-hospital mortality. Design, Setting, and Participants: A retrospective cohort study including adult medical inpatients receiving ceftriaxone with lansoprazole or another PPI in 13 hospitals in Ontario, Canada, was conducted from January 1, 2015, to December 31, 2021. Exposure: Lansoprazole during ceftriaxone treatment vs other PPIs during ceftriaxone treatment. Main Outcomes and Measures: The primary outcome was a composite of ventricular arrhythmia or cardiac arrest that occurred after hospital admission. The secondary outcome was all-cause in-hospital mortality. Propensity-score weighting was used to adjust for covariates including hospital site, demographic characteristics, comorbidities, risk factors for ventricular arrhythmia, illness severity, admitting diagnoses, and concomitant medications. Results: Of the 31 152 patients hospitalized on internal medicine wards who were treated with ceftriaxone while receiving a PPI, 16 135 patients (51.8%) were male, and the mean (SD) age was 71.7 (16.0) years. The study included 3747 patients in the lansoprazole group and 27 405 patients in the other PPI group. Ventricular arrhythmia or cardiac arrest occurred in 126 patients (3.4%) within the lansoprazole group and 319 patients (1.2%) within the other PPI group. In-hospital mortality occurred in 746 patients (19.9%) within the lansoprazole group and 2762 patients (10.1%) in the other PPI group. After weighting using propensity scores, the adjusted risk difference for the lansoprazole group minus other PPI group was 1.7% (95% CI, 1.1%-2.3%) for ventricular arrhythmia or cardiac arrest and 7.4% (95% CI, 6.1%-8.8%) for in-hospital mortality. Conclusions and Relevance: The findings of this cohort study suggest that combination therapy with lansoprazole and ceftriaxone should be avoided. More studies are needed to determine whether these findings could be replicated in other populations and settings.

Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Methodological and Reporting Quality of Noninferiority Randomized Controlled Trials Comparing Antiretroviral Therapies: A Systematic Review.

BACKGROUND: It is unclear whether the reporting quality of antiretroviral (ARV) noninferiority (NI) randomized controlled trials (RCTs) has improved since the CONSORT guideline release in 2006. The primary objective of this systematic review was assessing the methodological and reporting quality of ARV NI-RCTs. We also assessed reporting quality by funding source and publication year. METHODS: We searched Medline, Embase, and Cochrane Central from inception to 14 November 2022. We included NI-RCTs comparing ≥2 ARV regimens used for human immunodeficiency virus treatment or prophylaxis. We used the Cochrane Risk of Bias 2.0 tool to assess risk of bias. Screening and data extraction were performed blinded and in duplicate. Descriptive statistics were used to summarize data; statistical tests were 2 sided, with significance defined as P < .05. The systematic review was prospectively registered (PROSPERO CRD42022328586), and not funded. RESULTS: We included 160 articles reporting 171 trials. Of these articles, 101 (63.1%) did not justify the NI margin used, and 28 (17.5%) did not provide sufficient information for sample size calculation. Eighty-nine of 160 (55.6%) reported both intention-to-treat and per-protocol analyses, while 118 (73.8%) described missing data handling. Ten of 171 trials (5.9%) reported potentially misleading results. Pharmaceutical industry-funded trials were more likely to be double-blinded (28.1% vs 10.3%; P = .03) and to describe missing data handling (78.5% vs 59.0%; P = .02). The overall risk of bias was low in 96 of 160 studies (60.0%). CONCLUSIONS: ARV NI-RCTs should improve NI margin justification, reporting of intention-to-treat and per-protocol analyses, and missing data handling to increase CONSORT adherence.

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles: A Systematic Review.

Importance: Randomized clinical trials (RCTs) on COVID-19 are increasingly being posted as preprints before publication in a scientific, peer-reviewed journal. Objective: To assess time to journal publication for COVID-19 RCT preprints and to compare differences between pairs of preprints and corresponding journal articles. Evidence Review: This systematic review used a meta-epidemiologic approach to conduct a literature search using the World Health Organization COVID-19 database and Embase to identify preprints published between January 1 and December 31, 2021. This review included RCTs with human participants and research questions regarding the treatment or prevention of COVID-19. For each preprint, a literature search was done to locate the corresponding journal article. Two independent reviewers read the full text, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Time to publication was analyzed using a Cox proportional hazards regression model. Differences between preprint and journal article pairs in terms of outcomes, analyses, results, or conclusions were described. Statistical analysis was performed on October 17, 2022. Findings: This study included 152 preprints. As of October 1, 2022, 119 of 152 preprints (78.3%) had been published in journals. The median time to publication was 186 days (range, 17-407 days). In a multivariable model, larger sample size and low risk of bias were associated with journal publication. With a sample size of less than 200 as the reference, sample sizes of 201 to 1000 and greater than 1000 had hazard ratios (HRs) of 1.23 (95% CI, 0.80-1.91) and 2.19 (95% CI, 1.36-3.53) for publication, respectively. With high risk of bias as the reference, medium-risk articles with some concerns for bias had an HR of 1.77 (95% CI, 1.02-3.09); those with a low risk of bias had an HR of 3.01 (95% CI, 1.71-5.30). Of the 119 published preprints, there were differences in terms of outcomes, analyses, results, or conclusions in 65 studies (54.6%). The main conclusion in the preprint contradicted the conclusion in the journal article for 2 studies (1.7%). Conclusions and Relevance: These findings suggest that there is a substantial time lag from preprint posting to journal publication. Preprints with smaller sample sizes and high risk of bias were less likely to be published. Finally, although differences in terms of outcomes, analyses, results, or conclusions were observed for preprint and journal article pairs in most studies, the main conclusion remained consistent for the majority of studies.

Association of Linezolid With Risk of Serotonin Syndrome in Patients Receiving Antidepressants.

Importance: Linezolid has the potential to interact with some antidepressants, leading to serotonin syndrome. However, few empirical data support warnings for patients taking antidepressants to avoid linezolid. Objectives: To examine the incidence of serotonin syndrome in patients receiving oral linezolid and how concomitant antidepressant treatment changes this risk. Design, Setting, and Participants: This population-based, retrospective cohort study used linked administrative databases at ICES to collect data from outpatients 66 years or older in Ontario, Canada, who were prescribed oral linezolid for any duration from October 1, 2014, to January 1, 2021, with follow-up to 30 days (January 31, 2021). Exposures: The use of antidepressants while receiving linezolid therapy vs no antidepressant use while receiving linezolid therapy. Main Outcomes and Measures: The primary outcome was clinically significant serotonin syndrome based on a physician diagnosis, Sternbach criteria, or the Hunter Serotonin Toxicity Criteria within 30 days of starting oral linezolid treatment. Secondary outcomes were altered mental status, hospitalization, or death within 30 days of starting linezolid treatment. Results: The study included 1134 patients (age ranges, 66-69 years for 225 patients [19.8%], 70-79 years for 473 patients [41.7%], and ≥80 years for 436 patients [38.4%]; 595 [52.5%] male) who were prescribed linezolid. Of 1134 patients, 215 (19.0%) were also taking antidepressants. Serotonin syndrome occurred in fewer than 6 patients (<0.5%). The number of serotonin syndrome cases were fewer in the antidepressant group. In a propensity score-matched cohort, the adjusted risk difference for serotonin syndrome between the antidepressant group and the no antidepressant group was -1.2% (95% CI, -2.9% to 0.5%). There were similar rates of altered mental status, hospitalization, and death between the propensity score-matched groups. Conclusions and Relevance: In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely. Concurrent antidepressants did not significantly increase the risk of serotonin syndrome. These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction.

Staphylococcus aureus bacteremia mortality across country income groups: A secondary analysis of a systematic review.

OBJECTIVES: Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis. METHODS: We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics. RESULTS: A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T2 = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T2 = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC. CONCLUSION: In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap.

Bedspacing and clinical outcomes in general internal medicine: A retrospective, multicenter cohort study.

BACKGROUND: Admitting hospitalized patients to off-service wards ("bedspacing") is common and may affect quality of care and patient outcomes. OBJECTIVE: To compare in-hospital mortality, 30-day readmission to general internal medicine (GIM), and hospital length-of-stay among GIM patients admitted to GIM wards or bedspaced to off-service wards. DESIGN, PARTICIPANTS, AND MEASURES: Retrospective cohort study including all emergency department admissions to GIM between 2015 and 2017 at six hospitals in Ontario, Canada. We compared patients admitted to GIM wards with those who were bedspaced, using multivariable regression models and propensity score matching to control for patient and situational factors. KEY RESULTS: Among 40,440 GIM admissions, 10,745 (26.6%) were bedspaced to non-GIM wards and 29,695 (73.4%) were assigned to GIM wards. After multivariable adjustment, bedspacing was associated with no significant difference in mortality (adjusted hazard ratio 0.95, 95% confidence interval [CI]: 0.86-1.05, p = .304), slightly shorter median hospital length-of-stay (-0.10 days, 95% CI:-0.20 to -0.001, p = .047) and lower 30-day readmission to GIM (adjusted OR 0.89, 95% CI: 0.83-0.95, p = .001). Results were consistent when examining each hospital individually and outcomes did not significantly differ between medical or surgical off-service wards. Sensitivity analyses focused on the highest risk patients did not exclude the possibility of harm associated with bedspacing, although adverse outcomes were not significantly greater. CONCLUSIONS: Overall, bedspacing was associated with no significant difference in mortality, slightly shorter hospital length-of-stay, and fewer 30-day readmissions to GIM, although potential harms in high-risk patients remain uncertain. Given that hospital capacity issues are likely to persist, future research should aim to understand how bedspacing can be achieved safely at all hospitals, perhaps by strengthening the selection of low-risk patients.

What Is the Optimal Follow-up Length for Mortality in Staphylococcus aureus Bacteremia? Observations From a Systematic Review of Attributable Mortality.

Background: Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time. Methods: We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths. Results: Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%-89%) at 1 month and 62% (IQR, 58%-75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies. Conclusions: The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality. Clinical Trials Registration: PROSPERO CRD42021253891.

Staphylococcus aureus bacteraemia mortality: a systematic review and meta-analysis.

BACKGROUND: Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies. OBJECTIVES: We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time. DATA SOURCES: The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021. STUDY ELIGIBILITY CRITERIA: Human observational studies on patients with S. aureus bloodstream infection were included. PARTICIPANTS: The study analyzed data of patients with a positive blood culture for S. aureus. METHODS: Two independent reviewers extracted study data and assessed risk of bias using the Newcastle-Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates. RESULTS: A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%-12.1%) at 7 days, 13.3% (95% CI, 11.1%-15.8%) at 2 weeks, 18.1% (95% CI, 16.3%-20.0%) at 1 month, 27.0% (95% CI, 21.5%-33.3%) at 3 months, and 30.2% (95% CI, 22.4%-39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02-1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75-1.03 for 2001-2010; aOR: 0.82; 95% CI, 0.69-0.97 for 2011 onward). CONCLUSIONS: SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary.

How Generalizable Are Randomized Controlled Trials (RCTs) in Staphylococcus aureus Bacteremia? A Description of the Mortality Gap Between RCTs and Observational Studies.

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care.

Safety Profile of Linezolid in Older Adults With Renal Impairment: A Population-Based Retrospective Cohort Study.

Background: The objective of this study was to characterize the safety profile of linezolid in patients with renal impairment compared with patients without renal impairment. Methods: A population-based retrospective cohort study using linked administrative databases included patients aged 66 years or older in Ontario, Canadawho were prescribed linezolid from 2014 to 2021. Renal impairment was defined using baseline estimated glomerular filtration rate <30 mL/min/1.73 m2 or receipt of dialysis. The primary outcomes were change in platelet count and severe thrombocytopenia (platelet count <50 × 109/L) within 90 days. Secondary outcomes included bleeding, neutropenia, peripheral neuropathy, optic neuropathy, acidosis, serotonin syndrome, and mortality. Inverse probability of treatment weighting on propensity score was used to balance comparison groups on baseline health. Results: Of 625 patients, 98 (15.7%) patients had renal impairment. The mean (SD) platelet change was -88.3 (108.4) 109/L in the renal impairment group and -76.5 (109.8) 109/L in the no renal impairment group, with an adjusted mean difference of -29.4 (95% CI, -53.4 to -5.3; P = .0165). Severe thrombocytopenia occurred in 9.2% for the renal impairment group and 5.9% for the no renal impairment group, with an adjusted risk difference of 2.7% (95% CI, -3.1% to 8.6%; P = .3655). There were no significant differences in secondary outcomes between the 2 groups. Conclusions: Patients with renal impairment on linezolid therapy had a larger decrease in platelet count, but their risks for severe thrombocytopenia and bleeding were not significantly different than patients without renal impairment. Linezolid is likely safe in renal impairment without dose adjustment or drug level monitoring.